Inflammatory bowel diseases (IBD), such as ulcerative colitis and Crohn's disease, are characterized by chronic and relapsing inflammation of the intestine. Recent evidence indicates that IBD is due to a loss of tolerance to commensal intestinal flora in which the mucosal immune system can not differentiate between pathogens and commensal organisms. Therefore IBD patients develop immune recognition to normal flora which results in a gastrointestinal inflammatory response. The extent to which seroreactivity to normal flora develops is roughly correlated with disease duration and disease severity (Lodes et al., J Clin Invest., 113:1296-1306, 2004). More than 25 alleles have been identified that overlap between ulcerative colitis and Crohn's disease genetics (Umeno et al., Inflamm Bowel Dis. In press, 2011). These IBD genetic alleles converge on several common pathways that result in 1) Defects in epithelial integrity, 2) Defects in myeloid microbial responses and production of proinflammatory cytokines, and 3) Increased T-helper 17 cell and T-helper 1 cell responses. Studies show that most IBD patients have a spontaneous relapse and remission cycle where they achieve clinical remission at reasonable frequency but do not sustain remission for extended periods. This observation indicates the existence of as yet undefined mucosal homeostatic mechanisms that may drive the IBD remission phase (Schirbel et al., Expert Rev Gastroenterol Hepatol., 5(1):33-41, 2011). The identification of molecules and mechanisms involved in maintaining mucosal homeostasis would therefore be beneficial for driving as well as maintaining IBD remission.
CD83 is a highly conserved 45 kilodalton transmembrane glycoprotein that is predominantly expressed on the surface of dendritic cells and thymic epithelial cells. Additionally, CD83 is transiently expressed on the surface of other activated cells of the immune system and can also be found in a soluble form. Structural analysis of the predicted amino acid sequence of CD83 demonstrates that it is a member of the immunoglobulin super family indicating a role in the immune system. Literature reports suggests that soluble CD83 (sCD83) may play an immunomodulatory role due to the observation that sCD83 released by HCMV-infected mature dendritic cells inhibits T cell proliferation (Senechal et al., Blood., 103(11):4207-4215, 2004) and that sCD83 has a morphologic effect on the dendritic cell cytoskeleton (Kotzor et al., Immunobiology., 209(1-2):129-140, 2004). However, no ligand has been identified for CD83 and the function of CD83 remains poorly understood. Interestingly, CD83 gene expression is downregulated at the mucosal surface in human Crohn's disease (Silva et al., Dig. Dis. Sci., 53(7):1917-1928, 2008), suggesting that CD83 may be involved in the maintenance of mucosal homeostasis and therefore be a therapeutic target for modulating the immune system in IBD.
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